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Retinal inflammation is a central feature of ocular neovascular diseases such as diabetic retinopathy and retinopathy of prematurity, but the contribution of neutrophils to this process is not fully understood. We studied oxygen-induced retinopathy (OIR) which develops in two phases, featuring hyperoxia-induced retinal vaso-obliteration in phase I, followed by retinal neovascularization in phase II. As neutrophils are acute responders to tissue damage, we evaluated whether neutrophil depletion with an anti-Ly6G mAb administered in phase I OIR influenced retinal inflammation and vascular injury. Neutrophils were measured in blood and spleen via flow cytometry, and myeloperoxidase, an indicator of neutrophil activity, was evaluated in the retina using Western blotting. Retinal vasculopathy was assessed by quantitating vaso-obliteration, neovascularization, vascular leakage, and VEGF levels. The inflammatory factors, TNF, MCP-1, and ICAM-1 were measured in retina. In the OIR controls, neutrophils were increased in the blood and spleen in phase I but not phase II OIR. In OIR, the anti-Ly6G mAb reduced neutrophils in the blood and spleen, and myeloperoxidase, inflammation, and vasculopathy in the retina. Our findings revealed that the early rise in neutrophils in OIR primes the retina for an inflammatory and angiogenic response that promotes severe damage to the retinal vasculature.

VEGF was initially discovered due to its angiogenic activity and therefore named "vascular endothelial growth factor." However, its more recently discovered neurotrophic activity may be evolutionarily more ancient. Our previous work showed that all the changes produced by axotomy on the firing activity and synaptic inputs of abducens motoneurons were completely restored after VEGF administration. Therefore, we hypothesized that the lack of VEGF delivered by retrograde transport from the periphery should also affect the physiology of otherwise intact abducens motoneurons. For VEGF retrograde blockade, we chronically applied a neutralizing VEGF antibody to the lateral rectus muscle. Recordings of extracellular single-unit activity and eye movements were made in alert cats before and after the application of the neutralizing antibody. Our data revealed that intact, noninjured abducens motoneurons retrogradely deprived of VEGF exhibited noticeable changes in their firing pattern. There is a general decrease in firing rate and a significant reduction in eye position and eye velocity sensitivity (i.e., a decrease in the tonic and phasic components of their discharge, respectively). Moreover, by means of confocal immunocytochemistry, motoneurons under VEGF blockade showed a marked reduction in the density of afferent synaptic terminals contacting with their cell bodies. Altogether, the present findings demonstrate that the lack of retrogradely delivered VEGF renders abducens motoneurons into an axotomy-like state. This indicates that VEGF is an essential retrograde factor for motoneuronal synaptic drive and discharge activity.

The global propagation of SARS-CoV-2 leads to an unprecedented public health emergency. Despite that the lungs are the primary organ targeted by COVID-19, systemic endothelial inflammation and dysfunction is observed particularly in patients with severe COVID-19, manifested by elevated endothelial injury markers, endotheliitis, and coagulopathy. Here, we review the clinical characteristics of COVID-19 associated endothelial dysfunction; and the likely pathological mechanisms underlying the disease including direct cell entry or indirect immune overreactions after SARS-CoV-2 infection. In addition, we discuss potential biomarkers that might indicate the disease severity, particularly related to the abnormal development of thrombosis that is a fatal vascular complication of severe COVID-19. Furthermore, we summarize clinical trials targeting the direct and indirect pathological pathways after SARS-CoV-2 infection to prevent or inhibit the virus induced endothelial disorders., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The delivery of nitric oxide (NO)-an intrinsic cellular signaling molecule-is promising for disease treatment, in particular to vascular diseases, due to its endothelial-derived inherent nature. The limited diffusion distance of labile NO prompts researchers to develop various carriers and targeting methods for specific sites. In contrast to the apoptotic effect of NO, such as anticancer, delivering low NO concentration at the desired targeting area is still intricate in a physiological environment. In this study, the layer-by-layer assembled nanocoating is leveraged to develop a direct NO delivery platform to individual endothelial cells (ECs). NO can be localized to individual ECs via S-nitrosothiol-bound polyacrylic acid which is a polymer directly providing an endothelial-like constant level of NO. To increase angiogenic activation along with NO, VEGF is additionally applied to specific receptors on the cell surface. Notably, the survival and proliferation of ECs are significantly increased by a synergistic effect of NO and VEGF co-localized via nanocoating. Furthermore, the nanocoating remarkably promoted cell migration and tubule formation-prerequisites of angiogenesis. The proposed unique technology based on nanocoating demonstrates great potential for conferring desired angiogenic functions to individual ECs through efficient NO delivery., (© 2021 Wiley-VCH GmbH.)

Vascular endothelial growth factor-A (VEGF-A) is a critical angiogenic factor which is mainly secreted from podocytes and epithelial cells in kidney and plays an important role in renal pathophysiology. In recent years, functions of different isoforms of VEGF-A and the new secretion approach via extracellular vesicles (EVs) have been identified. Thus, further understanding are needed for the role of VEGF-A and its isoforms in renal injury and repair. In this review, we summarized the expression, secretion and regulation of VEGF-A, its biological function, and the role of different isoforms of VEGF-A in the development of different renal diseases. Meanwhile, the research progress of VEGF-A as diagnostic marker and therapeutic target for renal diseases were discussed.

Sjögren's syndrome (SS) which could lead to a disorder of our immune system is a chronic autoimmune disease characterized by invading exocrine glands such as salivary glands and lacrimal glands and other exocrine glands. Its common symptom is dry mouth and dry eyes, often accompanied by a large number of lymphocyte infiltrations and can involve other organs to cause complex clinical manifestations. In this study, we aimed at investigating the effect of QZF in SS, identifying the molecular mechanism in modulating autoimmune response, and determining the important roles of these factors' function as a modulator in the pathogenesis of SS. The NOD mice were utilized to establish the rats' model of Sjögren's syndrome. After 10 weeks' hydroxychloroquine and QZF in different dose interference, submandibular gland tissue was collected. The therapeutic effect of QZF on SS rats was identified, and the results suggest the comparable potential to hydroxychloroquine. In submandibular gland tissue, interleukin- (IL-) 17 was significantly lower in high-dose QZF than that in SS rats and the focal lymphocytes were highly attenuated. Moreover, we found that PI3K/Akt signals were activated and the downstream HIF-1 α /VEGF signals were enhanced in SS rats whose protein expression could be inhibited by QZF treatment. In addition, QZF could modulate autophagy in submandibular gland tissue and then inhibit the inflammation response and therefore facilitate the tissue repair., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Ping Zeng et al.)

Background: Microcirculation is essential for skin homeostasis and repair. A variety of growth factors have been identified as important regulators of wound healing. However, direct observation and longitudinal monitoring of skin remodeling in an unperturbed in vivo environment remains challenging. Methods: We report on non-invasive longitudinal imaging of the wound healing process in transgenic mice overexpressing vascular endothelial growth factor A (VEGF-A) in keratinocytes by means of large-scale optoacoustic microscopy (LSOM). This rapid, label-free, high throughput intravital microscopy method averts the use of dorsal skin-fold chambers, allowing for fully non-invasive repeated imaging of intact wounds with capillary resolution over field-of-view spanning several centimeters. Results: We observed VEGF-driven enhancement of dermal vascularization in ears, dorsal skin and healing wounds and quantified the hemoglobin content, fill fraction, vessel diameter and tortuosity. The in vivo findings were further corroborated by detailed side-by-side classical histological whole-mount vascular stainings and pan-endothelial CD31 immunofluorescence. Conclusion: The new approach is suitable for supplementing or replacing the cumbersome histological procedures in a broad range of skin regeneration and tissue engineering applications., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic factors include vascular endothelial growth factor (VEGF), angiopoietins, platelet-derived growth factor, transforming growth factor-β, and basic fibroblast growth factor. Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have recently been added to an important angiogenic factor. Accumulating evidence indicates associations between angiogenesis and chronic inflammatory skin diseases. Angiogenesis is deeply involved in the pathogenesis of psoriasis. VEGF, angiopoietins, tumor necrosis factor-a, interleukin-8, and interleukin-17 are unregulated in psoriasis and induce angiogenesis. Angiogenesis may be involved in the pathogenesis of atopic dermatitis, and in particular, mast cells are a major source of VEGF expression. Angiogenesis is an essential process in rosacea, which is induced by LL-37 from a signal cascade by microorganisms, VEGF, and MMP-3 from mast cells. In addition, angiogenesis by increased VEGF has been reported in chronic urticaria and hidradenitis suppurativa. The finding that VEGF is expressed in inflammatory skin lesions indicates that inhibition of angiogenesis is a useful strategy for treatment of chronic, inflammatory skin disorders.

Diabetic retinopathy (DR) has been regarded as a sight-threatening vascular complication of diabetes mellitus. Accumulating evidence has identified the involvement of long non-coding RNAs (lncRNAs) in DR pathogenesis. We aim to investigate the role and underlying mechanism of linc00174 in the DR process. Samples of human vitreous humour from proliferative DR and non-diabetic individuals were collected to examine the levels of linc00174. Human retinal microvascular endothelial cells (HRMECs) exposed with high glucose (HG) were employed to simulate the pathological statues of DR. Short hairpin RNA specifically targeting linc00174 was applied. CCK-8, transwell, and matrigel tube formation were performed to evaluate cell proliferation, migration, and angiogenesis. Bioinformatics analysis and luciferase reporter assay were conducted to verify the linc00174/miR-150-5p/vascular endothelial growth factor A (VEGFA) regulatory network. Western blotting was employed to determine the expression of VEGFA. Linc00174 was significantly elevated in patients with DR, as well as HG-stimulated HRMECs, of which knockdown repressed HG-induced proliferation, migration, and angiogenesis. miR-150-5p was identified as a downstream effector to be involved in linc00174-mediated protective effects. miR-150-5p directly bound to the 3' untranslated region of VEGFA. The linc00174/miR-150-5p/VEGFA axis was confirmed in retinal vascular dysfunction. The linc00174 deteriorates diabetic retinal microangiopathy via regulating miR-150-5p/VEGFA pathway, indicating a novel therapeutic target for DR treatment.

Oxygen is one of the important substances for the survival of most life systems on the earth, and plateau and underground burrow systems are two typical hypoxic environments. Small mammals living in hypoxic environments have evolved different adaptation strategies, which include increased oxygen delivery, metabolic regulation of physiological responses and other physiological responses that change tissue oxygen utilization. Multi-omics predictions have also shown that these animals have evolved different adaptations to extreme environments. In particular, vascular endothelial growth factor (VEGF) and erythropoietin (EPO), which have specific functions in the control of O 2 delivery, have evolved adaptively in small mammals in hypoxic environments. Naked mole-rats and blind mole-rats are typical hypoxic model animals as they have some resistance to cancer. This review primarily summarizes the main living environment of hypoxia tolerant small mammals, as well as the changes of phenotype, physiochemical characteristics and gene expression mode of their long-term living in hypoxia environment., Competing Interests: The authors declared that they have no conflicts of interest to this work., (© 2021 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Background: Previous studies have suggested essential roles of growth factors on the risk of Multiple Sclerosis (MS), but it remains undefined whether the effects are causal., Objective: We applied Mendelian randomization (MR) approaches to disentangle the causal relationship between genetically predicted circulating levels of growth factors and the risk of MS., Methods: Genetic instrumental variables for fibroblast growth factor (FGF) 23, growth differentiation factor 15 (GDF15), insulin growth factor 1 (IGF1), insulin-like growth factor binding proteins 3 (IGFBP3) and vascular endothelial growth factor (VEGF) were obtained from up-to-date genome-wide association studies (GWAS). Summary-level statistics of MS were obtained from the International Multiple Sclerosis Genetics Consortium, incorporating 14,802 subjects with MS and 26,703 healthy controls of European ancestry. Inverse-variance weighted (IVW) MR was used as the primary method and multiple sensitivity analyses were employed in this study., Results: Genetically predicted circulating levels of FGF23 were associated with risk of MS. The odds ratio (OR) of IVW was 0.63 (95% confidence interval [CI], 0.49-0.82; p < 0.001) per one standard deviation increase in circulating FGF23 levels. Weighted median estimators also suggested FGF23 associated with lower MS risk (OR = 0.67; 95% CI, 0.51-0.87; p = 0.003). While MR-Egger approach provided no evidence of horizontal pleiotropy (intercept = -0.003, p = 0.95). Results of IVW methods provided no evidence for causal roles of GDF1, IGF1, IGFBP3 and VEGF on MS risks, and additional sensitivity analyses confirmed the robustness of these null findings., Conclusion: Our results implied a causal relationship between FGF23 and the risk of MS. Further studies are warranted to confirm FGF23 as a genetically valid target for MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lu, Wu, Ma, Zhang and Sun.)

The study aimed to investigate the dynamic changes of percutaneous partial oxygen pressure during the development and evolution of a hypertrophic scar. Twenty cases of hypertrophic scar patients at different stages were selected. A percutaneous oxygen monitor was used to measure oxygen partial pressure in the scar and normal skin tissue at 14, 30, 60, and 90 days after surgery. The changes of oxygen partial pressure, tissue structure, HIF-1 α , and VEGF expression in the scar tissue were observed, and the correlation was analyzed. In the scar maturation process, with the prolongation of time, the partial oxygen pressure in the tissue increased gradually. The expression intensity of HIF-1 α and VEGF decreased gradually, HIF-1 α was positively correlated with VEGF ( r  = 0.98, P < 0.01), there was a negative correlation between oxygen partial pressure and HIF-1 α expression ( r  = -0.92, P < 0.01), and it was negatively correlated with VEGF ( r  = -0.88, P < 0.01). TcPO 2 measurement can be used to assess scar maturity; HIF-1 α and VEGF may play an essential role in regulating partial oxygen pressure in the scar tissue., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Wanle Qi et al.)

Theta and gamma rhythms in hippocampus are important to cognitive performance. The cognitive impairments following cerebral ischemia is linked with the dysfunction of theta and gamma oscillations. As the primary mechanism for learning and memory, synaptic plasticity is in connection with these neural oscillations. Although vascular endothelial growth factor (VEGF) is thought to protect synaptic function in the ischemia rats to relieve cognitive impairment, little has been done on its effect of neural dynamics with this process. The present study investigated whether the alternation of neural oscillations in the hippocampus of ischemia rats is one of the potential neuroprotective mechanisms of VEGF. Rats were treated with the intranasal administration of VEGF at 72 h following chronic global cerebral ischemia procedure. Then local field potentials (LFPs) in hippocampal CA1 and CA3 regions were recorded and analyzed. Our results showed that VEGF can improve the power of theta and gamma rhythms in CA1 region after ischemia. Chronic global cerebral ischemia reduced the theta-gamma phase-amplitude coupling (PAC) not only within CA1 area but also in the pathway from CA3 to CA1, while VEGF alleviated the decreased coupling strength. Despite these notable differences, there were no obvious changes in the PAC within CA3 region. Surprisingly, the ischemia state did not affect the phase-phase interaction of hippocampus. In conclusion, our findings demonstrated that VEGF enhanced the theta-gamma PAC strength of CA3-CA1 pathway in ischemia rats, which may futher improve the information transmission within the hippocampus. These results illustrated the potential electrophysiologic mechanism of VEGF on cognitive improvement., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by vascular dysplasia. Mutations of the endoglin (ENG) gene that encodes a co-receptor of the transforming growth factor β1 signaling pathway cause type I HHT. ENG is primarily expressed in endothelial cells (ECs), but its interaction with other key angiogenic pathways to control angiogenesis has not been well addressed. The aim of this study is to investigate ENG interplay with VEGFR2, FGFR1 and TIE2 in primary human ECs. ENG was knocked-down with siRNA in human umbilical vein ECs (HUVECs) and human lung microvascular ECs (HMVEC-L). Gene expression was measured by RT-qPCR and Western blotting. Cell signaling pathway activation was analyzed by detecting phosphor-ERK and phosphor-AKT levels. Cell migration and apoptosis were assessed using the Boyden chamber assay and the CCK-8 Kit, respectively. Loss of ENG in HUVECs led to significantly reduced expression of VEGFR2 but not TIE2 or FGFR1, which was also confirmed in HMVEC-L. HUVECs lacking ENG had significantly lower levels of active Rac1 and a substantial reduction of the transcription factor Sp1, an activator of VEGFR2 transcription, in nuclei. Furthermore, VEGF- but not bFGF- or angiopoietin-1-induced phosphor-ERK and phosphor-AKT were suppressed in ENG deficient HUVECs. Functional analysis revealed that ENG knockdown inhibited cell migratory but enhanced anti-apoptotic activity induced by VEGF. In contrast, bFGF, angiopoietin-1 and -2 induced HUVEC migration and anti-apoptotic activities were not affected by ENG knockdown. In conclusion, ENG deficiency alters the VEGF/VEGFR2 pathway, which may play a role in HHT pathogenesis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Peptic ulcers are one of the world's major gastrointestinal disorders, embracing both gastric and duodenal ulcers, and affecting 10% of the world population. The current study aimed to investigate the possible protective effect of tadalafil and pentoxifylline (PTX) on indomethacin-induced peptic ulcers. Male albino rats were divided into five groups: control group; ulcerated group; Indomethacin + Tadalafil, in which animals were pretreated with tadalafil orally before indomethacin; Indomethacin+ PTX, in which animals were pretreated with PTX orally before indomethacin; and Indomethacin + Tadafil + PTX. Indomethacin treatment revealed histopathological changes and ulcer scoring and ulcer index were markedly increased. Serum levels of prostaglandin and heme oxygenase-1 were significantly decreased. The ulcerogenic also induced marked oxidative stress as evident from the increased malondialdehyde, decreased in gastric glutathione content and superoxide dismutase activity, while the gastric myeloperoxidase was increased. Gastric nitric oxide content was decreased and the expression of vascular endothelial growth factor was downregulated while the tumor necrosis factor α (TNF-α) level was dramatically increased. Pretreatment of the ulcerative group by either tadalafil or PTX or their combination improved all these pathological changes. Tadalafil or PTX may have a role in protecting gastric mucosa damage caused by indomethacin which may be useful in the future for the treatment of gastric ulceration.

mTOR inhibitors offer advantages after kidney transplantation including antiviral and antitumor activity besides facilitating low calcineurin inhibitor exposure to reduce nephrotoxicity. Concerns about adverse effects due to antiproliferative and antiangiogenic properties have limited their clinical use particularly early after transplantation. Interference with vascular endothelial growth factor (VEGF)-A, important for physiologic functioning of renal endothelial cells and tubular epithelium, has been implicated in detrimental renal effects of mTOR inhibitors. Low doses of Rapamycin (loading dose 3 mg/kg bodyweight, daily doses 1.5 mg/kg bodyweight) were administered in an allogenic rat kidney transplantation model resulting in a mean through concentration of 4.30 ng/mL. Glomerular and peritubular capillaries, tubular cell proliferation, or functional recovery from preservation/reperfusion injury were not compromised in comparison to vehicle treated animals. VEGF-A, VEGF receptor 2, and the co-receptor Neuropilin-1 were upregulated by Rapamycin within 7 days. Rat proximal tubular cells (RPTC) responded in vitro to hypoxia with increased VEGF-A and VEGF-R1 expression that was not suppressed by Rapamycin at therapeutic concentrations. Rapamycin did not impair proliferation of RPTC under hypoxic conditions. Low-dose Rapamycin early posttransplant does not negatively influence the VEGF network crucial for recovery from preservation/reperfusion injury. Enhancement of VEGF signaling peritransplant holds potential to further improve outcomes., (© 2021. The Author(s).)

Ischemic retinal dystrophies are leading causes of acquired vision loss. Although the dysregulated expression of the hypoxia-responsive VEGF-A is a major driver of ischemic retinopathies, implication of additional VEGF-family members in their pathogenesis has led to the development of multivalent anti-angiogenic tools. Designed as a decoy receptor for all ligands of VEGFR1 and VEGFR2, Aflibercept is a potent anti-angiogenic agent. Notwithstanding, the molecular mechanisms mediating Aflibercept's efficacy remain only partially understood. Here, we used the oxygen-induced retinopathy (OIR) mouse as a model system of pathological retinal vascularization to investigate the transcriptional response of the murine retina to hypoxia and of the OIR retina to Aflibercept. While OIR severely impaired transcriptional changes normally ensuing during retinal development, analysis of gene expression patterns hinted at alterations in leukocyte recruitment during the recovery phase of the OIR protocol. Moreover, the levels of Angiopoietin-2, a major player in the progression of diabetic retinopathy, were elevated in OIR tissues and consistently downregulated by Aflibercept. Notably, GO term, KEGG pathway enrichment, and expression dynamics analyses revealed that, beyond regulating angiogenic processes, Aflibercept also modulated inflammation and supported synaptic transmission. Altogether, our findings delineate novel mechanisms potentially underlying Aflibercept's efficacy against ischemic retinopathies., (© 2021. The Author(s).)

Diabetic retinopathy is one of the leading causes of vision loss and blindness. Extensive preclinical and clinical evidence exists for both vascular and neuronal pathology. However, the relationship of these changes in the neurovascular unit and impact on vision remains to be determined. Here, we investigate the role of tight junction protein occludin phosphorylation at S490 in modulating barrier properties and its impact on visual function. Conditional vascular expression of the phosphorylation-resistant Ser490 to Ala (S490A) form of occludin preserved tight junction organization and reduced vascular endothelial growth factor (VEGF)-induced permeability and edema formation after intraocular injection. In the retinas of streptozotocin-induced diabetic mice, endothelial-specific expression of the S490A form of occludin completely prevented diabetes-induced permeability to labeled dextran and inhibited leukostasis. Importantly, vascular-specific expression of the occludin mutant completely blocked the diabetes-induced decrease in visual acuity and contrast sensitivity. Together, these results reveal that occludin acts to regulate barrier properties downstream of VEGF in a phosphorylation-dependent manner and that loss of inner blood-retinal barrier integrity induced by diabetes contributes to vision loss., (© 2021 by the American Diabetes Association.)

Diabetes is a worldwide emergency. Its chronic complications impose a heavy burden on patients, health systems, and on society as a whole. Diabetic retinopathy is one of the most common and serious complications of diabetes, and an established risk factor for blindness in adults. Over 15 years of investigation led to the identification of vascular endothelial growth factor (VEGF) as a main pathogenic factor in diabetic retinopathy and to the introduction of highly effective anti-VEGF-based therapies, such as the monoclonal antibody bevacizumab or its fragment ranibizumab, which helped to prevent diabetes-related blindness in millions of patients. Recently, a pathogenic role for uncontrolled increases in the extracellular ATP concentration (eATP) and for overactivation of the purinergic receptor P2X7 (P2X7R) has been suggested. The P2X7R is an eATP-gated plasma membrane channel expressed in multiple tissues and organs, with a pleiotropic function in inflammation, immunity, cancer, and hormone and growth factor release. P2X7R stimulation or overexpression positively regulate the secretion and buildup of VEGF, thus promoting neo-angiogenesis in a wide variety of disease processes. In this review, we explore current evidence that supports the role of P2X7R receptor signaling in the pathogenesis of diabetic retinopathy, as well as the most appealing current therapeutical options for P2X7R targeting.

The dynamics of tumor growth and associated events cover multiple time and spatial scales, generally including extracellular, cellular and intracellular modifications. The main goal of this study is to model the biological and physical behavior of tumor evolution in presence of normal healthy tissue, considering a variety of events involved in the process. These include hyper and hypoactivation of signaling pathways during tumor growth, vessels' growth, intratumoral vascularization and competition of cancer cells with healthy host tissue. The work addresses two distinctive phases in tumor development-the avascular and vascular phases-and in each stage two cases are considered-with and without normal healthy cells. The tumor growth rate increases considerably as closed vessel loops (anastomoses) form around the tumor cells resulting from tumor induced vascularization. When taking into account the host tissue around the tumor, the results show that competition between normal cells and cancer cells leads to the formation of a hypoxic tumor core within a relatively short period of time. Moreover, a dense intratumoral vascular network is formed throughout the entire lesion as a sign of a high malignancy grade, which is consistent with reported experimental data for several types of solid carcinomas. In comparison with other mathematical models of tumor development, in this work we introduce a multiscale simulation that models the cellular interactions and cell behavior as a consequence of the activation of oncogenes and deactivation of gene signaling pathways within each cell. Simulating a therapy that blocks relevant signaling pathways results in the prevention of further tumor growth and leads to an expressive decrease in its size (82% in the simulation)., Competing Interests: The authors have declared that no competing interests exist.

Aims: Postmenopausal osteoporosis (PMOP) is a growing health problem affecting many postmenopausal women. This study intended to identify the role of dexmedetomidine (Dex) in osteoporosis (OP)., Main Methods: Microarray analysis was performed for the gene expression profiles of PMOP patients and postmenopausal healthy volunteers, and the most differentially expressed microRNA (miR)-361-5p was verified in clinic, and its diagnostic value in PMOP patients was analyzed. After establishment of OP model by ovariectomy, Dex treatment and overexpression of miR-361-5p or vascular endothelial growth factor A (VEGFA) were performed in OP rats or isolated bone marrow mesenchymal stem cells (BMSCs). Bone mineral density (BMD) related indexes and levels of osteogenesis-angiogenesis related genes were measured. The apoptosis and osteogenic differentiation of BMSCs were detected. After human umbilical vein endothelial cells (HUVECs) and BMSCs were cocultured, the angiogenesis of BMSCs was detected by Matrigel-based angiogenesis experiment., Key Findings: miR-361-5p was highly expressed in PMOP patients and OP rats, with good diagnostic effect on PMOP. After Dex treatment, the expressions of miR-361-5p, VEGFA, BMD related indexes were increased in OP rats. In BMSCs, level of osteogenesis-angiogenesis related genes were increased after adding Dex, and the apoptosis was decreased after coculture of HUVECs and BMSCs. miR-361-5p could target VEGFA. After miR-361-5p overexpression + Dex treatment, the indexes related to osteogenesis and angiogenesis in OP rats and BMSCs were decreased, which were reversed after further overexpressing VEGFA., Significance: Dex can enhance VEGFA by inhibiting miR-361-5p, and then promote osteogenesis-angiogenesis, thus providing potential targets for PMOP treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Anterior cruciate ligament transection surgery (ACLT)-induced OA model was often used to investigate the molecular mechanism of knee osteoarthritis (KOA). Researches have shown that vascular endothelial growth factor (VEGF) played an important role in OA. The present study aimed to investigate the pathological changes after ACLT surgery and reveal the expression characteristics of the VEGF-A/VEGFR2 signaling pathway in this model., Methods: Moderate KOA model was established by ACLT, and 1, 2, 4, 8, and 12 weeks after surgery, hematoxylin-eosin (HE) and Safranin-O(S-O) staining were used to detect the pathological changes in mouse knee cartilage, and the matrix biomarkers A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5(ADAMTS5), Collagen II (COL-II) were detected using immunohistochemistry (IHC), CD31 was detected by immunofluorescence (IF) to show the vascular invasion in cartilage, and proteins expression of VEGF-A pathway were detected by Western blot (WB). Meanwhile, the inflammatory biomarkers cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in cartilage were detected by WB., Results: ACLT surgery can lead to degeneration of cartilage in mice, and the characteristics of the lesion were time-dependent. The ADAMTS5-positive cells increased while COL-II decreased in OA cartilage with time, and new blood vessels labeled by CD31 can be seen from 1 week in OA cartilage, and increased in 8 and 12 weeks. The expression of VEGF-A, VEGFR2, COX-2, and iNOS were higher than control groups, which were basically consistent with the degree of osteoarthritis., Conclusions: The degenerative degree of articular cartilage was time-dependent; angiogenesis and inflammation were important pathological changes of cartilage in KOA. The expression of the VEGF-A/VEGFR2 signaling pathway was basically correlated with the degree of KOA.

Cervical epithelial cells play a central role in cervical remodeling (CR) during pregnancy and cervical events during menstrual cycle, including mounting physical and immunological barriers, proliferation and differentiation, maintenance of fluid balance, and likely in withstanding the mechanical force exerted by the growing fetus prior to term. In the present study, we attempt to decipher the specific roles of VEGF in fetal human cervical epithelial cells by delineating VEGF signature genes using RNA sequencing in order to characterize the specific biological effects of VEGF in these cells.Out of a total of 25,000 genes screened, 162 genes were found to be differentially expressed in human cervical epithelial cells, of which 12 genes were found to be statistically significantly differentially expressed. The differentially expressed genes (162) were categorized by biological function, which included (1) proliferation, (2) immune response, (3) structure/matrix, (4) mitochondrial function, and (5) cell adhesion/communication and others (pseudogenes, non-coding RNA, miscellaneous genes, and uncharacterized genes). We conclude that VEGF plays a key role in CR by altering the expression of genes that regulate proliferation, immune response, energy metabolism and cell structure, and biological processes that are essential to development and likely CR.

Background: Interleukin (IL)-17A possesses biological activities to promote vascular endothelial cell migration and microvessel development., Objective: To clarify which angiogenic factors are involved in IL-17A-modified angiogenesis-related functions of vascular endothelial cell migration and microtube development or not., Methods: The potential contribution of various angiogenic stimulators to in vitro angiogenic activities of IL-17A was assessed with both modified Boyden Chemotaxicell chamber assay and in vitro angiogenesis assay., Results: The addition of a neutralizing antibody (Ab) for hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF)-A to the upper and lower compartments in a modified Boyden Chemotaxicell chamber significantly attenuated human dermal microvascular endothelial cell (HMVEC) migration elicited by IL-17A. Moreover, IL-17A-induced capillary-like microvessel development in human umbilical vein endothelial cell (HUVEC) and human dermal fibroblast (HDF) co-culture system was significantly impaired by a neutralizing Ab against HGF, bFGF, VEGF-A, cysteine-x-cysteine ligand 8 (CXCL8)/IL-8 or cysteine-x-cysteine (CXC) chemokine receptor (CXCR)-2., Conclusion: Our findings demonstrate the involvement of HGF, bFGF, VEGF-A and/or CXCL8/IL-8, to various degrees, in migration and microvessel development of vascular endothelial cells mediated by IL-17A.

Purpose: The purpose of this study was to observe the effects of circHIPK3on the proliferation and apoptosis of ovarian cancer cells, and to further explore the potential mechanism therein., Methods: CircHIPK3 was determined in the carcinoma tissues, normal adjacent tissues, and also in ovarian cancer cells via RT-PCR. The proliferation and apoptosis of cells were observed via colony-forming assay, 5-ethynyl-2'-deoxyuridine (EdU) staining and Western blotting. Moreover, the effect of the inhibition of circHIPK3 on the in vivo growth of ovarian cancer cells was detected using subcutaneous tumorigenesis assay. Finally, the effect of circHIPK3 on the expression of the micro ribonucleic acid (miR)-7/vascular endothelial growth factor (VEGF) signaling pathway in ovarian cancer cells was examined., Results: CircHIPK3 in the carcinoma tissues was obviously higher than that in normal adjacent tissues. SKOV3 cell lines transfected with circHIPK3 inhibitor exhibited declined number of colonies. The inhibition of circHIPK3 distinctly suppressed the expression of B-cell lymphoma 2 (Bcl-2) and raised that of Bcl-2 associated X protein (Bax). Besides, the inhibition of circHIPK3 obviously weakened the tumorigenicity of ovarian cancer cells subcutaneously transplanted. Finally, it was found that miR-7 declined obviously and VEGF rose distinctly in the carcinoma tissues, and the in vitro assay verified the obvious increase in the expression of miR-7 and the prominently inhibited VEGF protein expression in the ovarian cancer cells with the inhibition of circHIPK3., Conclusions: CircHIPK3 has an obviously increased expression level in the carcinoma tissues of ovarian cancer patients, and the inhibition of circHIPK3 can activate the miR-7-mediated decline in the expression of VEGF to repress the proliferation and promote the apoptosis of ovarian cancer cells.

Mesenchymal stem cells (MSCs) have been identified in many adult tissues. MSCs can regenerate through cell division or differentiate into adipocytes, osteoblasts and chondrocytes. As a result, MSCs have become an important source of cells in tissue engineering and regenerative medicine for bone tissue and cartilage. Several epigenetic factors are believed to play a role in MSCs differentiation. Among these, microRNA (miRNA) regulation is involved in the fine modulation of gene expression during osteogenic/chondrogenic differentiation. It has been reported that miRNAs are involved in bone homeostasis by modulating osteoblast gene expression. In addition, countless evidence has demonstrated that miRNAs dysregulation is involved in the development of osteoporosis and bone fractures. The deregulation of miRNAs expression has also been associated with several malignancies including bone cancer. In this context, bone-associated circulating miRNAs may be useful biomarkers for determining the predisposition, onset and development of osteoporosis, as well as in clinical applications to improve the diagnosis, follow-up and treatment of cancer and metastases. Overall, this review will provide an overview of how miRNAs activities participate in osteogenic/chondrogenic differentiation, while addressing the role of miRNA regulatory effects on target genes. Finally, the role of miRNAs in pathologies and therapies will be presented., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Osteoarthritis (OA) is a worldwide musculoskeletal disorder. However, disease-modifying therapies for OA are not available. Here, we aimed to characterize the molecular signatures of OA and to identify novel therapeutic targets and strategies to improve the treatment of OA., Methods: We collected genome-wide transcriptome data performed on 132 OA and 74 normal human cartilage or synovium tissues from 7 independent datasets. Differential gene expression analysis and functional enrichment were performed to identify genes and pathways that were dysregulated in OA. The computational drug repurposing method was used to uncover drugs that could be repurposed to treat OA., Results: We identified several pathways associated with the development of OA, such as extracellular matrix organization, inflammation, bone development, and ossification. By protein-protein interaction (PPI) network analysis, we prioritized several hub genes, such as JUN, CDKN1A, VEGFA, and FOXO3. Moreover, we repurposed several FDA-approved drugs, such as cardiac glycosides, that could be used in the treatment of OA., Conclusions: We proposed that the hub genes we identified would play a role in cartilage homeostasis and could be important diagnostic and therapeutic targets. Drugs such as cardiac glycosides provided new possibilities for the treatment of OA.

Neovascularization is usually initialized from an existing normal vasculature and the biomechanical microenvironment of endothelial cells (ECs) in the initial stage varies dramatically from the following process of neovascularization. Although there are plenty of models to simulate different stages of neovascularization, an in vitro 3D model that capitulates the initial process of neovascularization under the corresponding stimulations of normal vasculature microenvironments is still lacking. Here, we reconstructed an in vitro 3D model that mimics the initial event of neovascularization (MIEN). The MIEN model contains a microfluidic sprouting chip and an automatic control, highly efficient circulation system. A functional, perfusable microchannel coated with endothelium was formed and the process of sprouting was simulated in the microfluidic sprouting chip. The initially physiological microenvironment of neovascularization was recapitulated with the microfluidic control system, by which ECs would be exposed to high luminal shear stress, physiological transendothelial flow, and various vascular endothelial growth factor (VEGF) distributions simultaneously. The MIEN model can be readily applied to the study of neovascularization mechanism and holds a potential promise as a low-cost platform for drug screening and toxicology applications.

Background: Prostate cancer (PCa) is the second most common type of male cancer in western. Despite key roles of brain-specific angiogenesis inhibitor 1-associated protein like 2 (BAIAP2L2) in several cancers, the function of BAIAP2L2 in PCa is never reported., Objective: We aimed to investigate the role of BAIAP2L2 in the progression of PCa and decipher the underlying mechanisms., Methods: RNA sequencing data from TCGA database were used to evaluate the expression of BAIAP2L2 in PCa. Survival analysis and Cox regression model analysis were conducted to evaluate the prognostic value of BAIAP2L2. BAIAP2L2-associated pathways were preliminary analyzed by Gene Set Enrichment Analysis (GSEA) method and confirmed by western blot assays. Cell proliferation and transwell assays were performed to determine biological behaviors in BAIAP2L2 knocked-down or overexpressed PCa cell lines including LNCaP and PC-3 cells., Results: In our study, BAIAP2L2 was significantly up-regulated in PCa tissues and cell lines and independently associated with the poor prognosis of PCa patients. Knockdown of BAIAP2L2 notably repressed proliferation, migration and invasion of PCa cells. And overexpression of BAIAP2L2 obtained the contrary results. Mechanically, GSEA method and western blot results of key molecules in signaling pathways implicated that the depletion of BAIAP2L2 inactivated the vascular endothelial growth factors (VEGFs) and induced apoptosis signaling pathways in PCa cells., Conclusions: Overall, these findings revealed that BAIAP2L2 may support tumorigenesis and malignant development of prostate cancer cells via VEGF and apoptosis signaling pathways, and it could be considered as a promising biomarker and independent prognostic predictor of prostate cancer.

Dementia is one of the most disabling non-motor symptoms in Parkinson's disease (PD). Unlike in Alzheimer's disease, the vascular pathology in PD is less documented. Due to the uncertain role of commonly investigated metabolic or vascular factors, e.g., hypertension or diabetes, other factors corresponding to PD dementia have been proposed. Associated dysautonomia and dopaminergic treatment seem to have an impact on diurnal blood pressure (BP) variability, which may presumably contribute to white matter hyperintensities (WMH) development and cognitive decline. We aim to review possible vascular and metabolic factors: Renin-angiotensin-aldosterone system, vascular endothelial growth factor (VEGF), hyperhomocysteinemia (HHcy), as well as the dopaminergic treatment, in the etiopathogenesis of PD dementia. Additionally, we focus on the role of polymorphisms within the genes for catechol- O -methyltransferase ( COMT ), apolipoprotein E ( APOE ), vascular endothelial growth factor ( VEGF ), and for renin-angiotensin-aldosterone system components, and their contribution to cognitive decline in PD. Determining vascular risk factors and their contribution to the cognitive impairment in PD may result in screening, as well as preventive measures.

SARS-CoV-2 virus has infected more than 92 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Using a rhesus macaque model of SARS-CoV-2 infection, we have characterized the transcriptional signatures induced in the lungs of juvenile and old macaques following infection. Genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated, as also seen in lungs of macaques with tuberculosis. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. Together, our transcriptomic studies have delineated disease pathways that improve our understanding of the immunopathogenesis of COVID-19.

Objective: Infantile hemangiomas (IHs) are the most common benign tumors in infancy. The purpose of this study was to study the effects of propranolol on the function of human umbilical vein endothelial cells (HUVECs), in order to preliminarily elucidate the mechanism of propranolol in the treatment of IHs., Methods: HUVECs were treated with different concentrations of propranolol (30  μ M, 60  μ M, 90  μ M, and 120  μ M) with or without VEGF. Their proliferation, migration, invasion, adhesion, and tube formation ability were tested by using CCK-8, wound healing assay, transwell, cell adhesion assay, and tube formation assay. The expressions of HUVECs angiogenesis signaling molecules pERK/ERK, pAKT/AKT, p-mTOR/mTOR, and pFAK/FAK were detected by Western blot., Results: Compared with the control group, propranolol could significantly inhibit the proliferation, migration, invasion, adhesion, and tube formation of HUVECs. Further studies showed that it could not only inhibit the migration, invasion, and tube formation ability of HUVECs after VEGF induction but also inhibit the phosphorylated protein expressions of angiogenesis-related signaling molecules like AKT, mTOR, ERK, and FAK in HUVECs, with a concentration-dependent inhibitory effect., Conclusion: Propranolol can inhibit the proliferation, migration, invasion, adhesion, and tube formation of hemangioma endothelial cells; block VEGF-mediated angiogenesis signaling pathway; suppress the expressions of downstream angiogenesis-related signaling molecules; and ultimately achieve the effect of treatment of IHs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Weili Yuan and Xukai Wang.)

Excessive tumour growth results in a hypoxic environment around cancer cells, thus inducing tumour angiogenesis, which refers to the generation of new blood vessels from pre-existing vessels. This mechanism is biologically and physically complex, with various mathematical simulation models proposing to reproduce its formation. However, although temporary vessel regression is clinically known, few models succeed in reproducing this phenomenon. Here, we developed a three-dimensional simulation model encompassing both angiogenesis and tumour growth, specifically including angiopoietin. Angiopoietin regulates both adhesion and migration between vascular endothelial cells and wall cells, thus inhibiting the cell-to-cell adhesion required for angiogenesis initiation. Simulation results showed a regression, i.e. transient decrease, in the overall length of new vessels during vascular network formation. Using our model, we also evaluated the efficacy of administering the drug bevacizumab. The results highlighted differences in treatment efficacy: (1) earlier administration showed higher efficacy in inhibiting tumour growth, and (2) efficacy depended on the treatment interval even with the administration of the same dose. After thorough validation in the future, these results will contribute to the design of angiogenesis treatment protocols.

Metastasis remains the major obstacle to improved survival for breast cancer patients. Downregulation of FOXO3a transcription factor in breast cancer is causally associated with the development of metastasis through poorly understood mechanisms. Here, we report that FOXO3a is functionally related to the inhibition of VEGF-A/NRP1 signaling and to the consequent suppression of breast cancer metastasis. We show that FOXO3a directly induces miR-29b-2 and miR-338 expression. Ectopic expression of miR-29b-2/miR-338 significantly suppresses EMT, migration/invasion, and in vivo metastasis of breast cancer. Moreover, we demonstrate that miR-29b-2 directly targets VEGF-A while miR-338 directly targets NRP1, and show that regulation of miR-29b-2 and miR-338 mediates the ability of FOXO3a to suppress VEGF-A/NRP1 signaling and breast cancer metastasis. Clinically, our results show that the FOXO3a-miR-29b-2/miR-338-VEGF-A/NRP1 axis is dysregulated and plays a critical role in disease progression in breast cancer. Collectively, our findings propose that FOXO3a functions as a metastasis suppressor, and define a novel signaling axis of FOXO3a-miRNA-VEGF-A/NRP1 in breast cancer, which might be potential therapeutic targets for breast cancer.

The number of patients with exudative age-related macular degeneration, diabetic retinopathy and retinal vein occlusion is expected to rise in proportion with the aging of the population and increasing diabetes patients. Also, they are the most common diseases caused by intraocular neovascularization and are often difficult to treat. Currently, anti-vascular endothelial growth factor (VEGF) therapy has been developed and has demonstrated excellent results in treating macular edema, and many patients have avoided blindness. Unfortunately, there are problems with cases that do not respond to the anti-VEGF drugs and complications of administration. It is necessary to deepen the understanding of the physiological and pathological retinal roles of VEGF and to optimize the anti-VEGF therapy. There are also no drugs indicated for the regression of neovascularization itself. The solution to this problem is to develop novel therapies targeting other than VEGF. In this symposium review, we introduce the roles of VEGF in the ischemic retina and anti-angiogenic factors as promising therapeutic targets.

Objective: To analyze the effects of the Human Chorionic Gonadotropin beta (β-hCG) and the VEGF-MEK/ERK signaling pathway on villi angiogenesis in early missed abortion., Methods: A total of 12 cases of women with missed abortion and 12 cases of women who had induced abortion voluntarily without any disease were included in the present study. The age, pregnancy time and gestation period in the control group corresponded to the missed abortion group. Wes Simple Western system and qRT-PCR were used to detect the expression of VEGF-MEK/ERK signaling pathway related proteins and genes in villous. Radioimmunoassay and Enzyme-linked immunosorbent assay were used to detect β-hCG and VEGF levels in serum. The microvascular density (MVD) in villous tissue was analyzed by immunohistochemical staining., Results: The levels of β-hCG and VEGF in serum, the expression of VEGF-MEK/ERK signaling pathway and MVD in villous tissue of the missed abortion group were lower than those of the control group. In addition, compared with the control group, the layers of trophoblasts of the villous tissue in the missed abortion group became thinner significantly, the number of cells reduced, the cell structures were disorganized, and parts of the trophoblast cells were absent. Correlational analysis showed that the protein expression of ERK1/2 was positively correlated with MVD in missed abortion group., Conclusions: Our results reveal that decreased production of β-hCG in early pregnant women could down-regulate the expression of VEGF-MEK/ERK signal pathway, then reduce angiogenesis and eventually leading to the abnormal angiogenesis of villous, which may be an important mechanism of missed abortion., Competing Interests: Declaration of competing interest The authors declare that there are no conflict of interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: We aimed at investigating the expression level of vascular endothelial growth factor-A (VEGF-A) in patients with primary Sjögren's Syndrome (pSS) and evaluating the relationship between serum VEGF-A and the laboratory indicators that are associated with it in pSS., Methods: The VEGF-A levels were measured by ELISA in a total of 88 participants, including 58 patients with pSS and 30 healthy people. The VEGF-A levels between two groups were analyzed., Results: The serum levels of VEGF-A in pSS and control groups were 175.50 (112.00,296.50) pg/mL and 181.50 (155.25,288.50) pg/mL, without statistically significant difference. The associations were found between serum levels of VEGF-A with C reactive protein (CRP) (r=0.265, P <0.05), white blood cells (WBC) (r=0.302, P<0.05), neutrophils (NEUT) (r=0.349, P <0.05), platelets(PLT) (r=0.276, P <0.05), complement 3 (C3) (r=0.477, P<0.05), complement 4 (C4) (r=0.387, P <0.05) and CA19-9 (r=0.392, P <0.05). Among these laboratory indicators, VEGF-A was correlated with platelets and complement 4 in patients with pSS., Conclusions: In patients with pSS, the levels of VEGF-A were independently influenced by the levels of platelet and complement 4, which indicated the intermodulation between the growth factor and immune system in the autoimmune disease., (© 2020 by the Association of Clinical Scientists, Inc.)

The blood vessel growth inhibitor bevacizumab targets vascular endothelial growth factor (VEGF), a crucial regulator of angiogenesis. Recently, small extracellular vesicles (sEVs) have been demonstrated to be important vehicles in the transport of growth factors to target cells. In this study, we isolated primary carcinoma-associated fibroblasts (CAFs) from four human oral squamous cell carcinoma (OSCC) specimens. Compared with other non-extracellular vesicle components, CAF-derived sEVs were found to be the main regulators of angiogenesis. The ability of CAF sEVs to activate VEGF receptor 2 (VEGFR2) signaling in human umbilical vein endothelial cells (HUVEC) was dependent on the association between sEVs and VEGF. In addition, sEV-bound VEGF secreted by CAFs further activated VEGFR2 signaling in HUVEC in a bevacizumab-resistant manner. VEGF was found to interact with heparan sulfate proteoglycans on the CAF sEV surface and could be released by heparinase I/III. The bioactivity of the dissociated VEGF was retained in vitro and in vivo and could be neutralized by bevacizumab. These findings suggest that the combined use of heparinase and bevacizumab might inhibit angiogenesis in patients with high levels of sEV-bound VEGF., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: The present study aims to investigate the antihypertensive effect and the underlying mechanism of GAO-ZI-YAO, one of the traditional Chinese medicines, in elderly spontaneous hypertensive rats (SHR)., Methods: 12-month-old male SHRs were randomly divided into five groups on the basis of treatment with different doses of GAO-ZI-YAO or angiotensin II receptor-1 blocker (ARB, Irbesartan) for four weeks. Systolic blood pressure (SBP), and serum levels of nitric oxide (NO), endothelin-1 (ET-1), angiotensin II (Ang II), vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-2, IL-6, and tumor necrotic factor (TNF)-α were measured. The pathological changes of ventricular muscle and thoracic aorta were observed by hematoxylin-eosin staining (H&E)., Results: GAO-ZI-YAO treatment reduced SBP in a dose-dependent manner accompanied by the inhibition of the development of cardiovascular remodeling. Although GAO-ZI-YAO treatment markedly increased serum levels of NO and suppressed serum levels of Ang II, this medicine did not affect the serum levels of ET-1 and VEGF. In addition, GAO-ZI-YAO also inhibited inflammatory response parameters (inflammatory cell infiltration in cardiac tissues and serum levels of IL-1β, IL-2, IL-6, and TNF-α) in a dose-dependent manner., Conclusion: GAO-ZI-YAO exerts antihypertensive and anti-cardiovascular-remodeling effects in elderly SHR, which may be through regulation of NO, Ang II production, and inflammation., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Arterial networks enlarge in response to increase in tissue metabolism to facilitate flow and nutrient delivery. Typically, the transition of a growing artery with a small diameter into a large caliber artery with a sizeable diameter occurs upon the blood flow driven change in number and shape of endothelial cells lining the arterial lumen. Here, using zebrafish embryos and endothelial cell models, we describe an alternative, flow independent model, involving enlargement of arterial endothelial cells, which results in the formation of large diameter arteries. Endothelial enlargement requires the GEF1 domain of the guanine nucleotide exchange factor Trio and activation of Rho-GTPases Rac1 and RhoG in the cell periphery, inducing F-actin cytoskeleton remodeling, myosin based tension at junction regions and focal adhesions. Activation of Trio in developing arteries in vivo involves precise titration of the Vegf signaling strength in the arterial wall, which is controlled by the soluble Vegf receptor Flt1.

Glioblastoma and other brain or CNS malignancies (like neuroblastoma and medulloblastoma) are difficult to treat and are characterized by excessive vascularization that favors further tumor growth. Since the mean overall survival of these types of diseases is low, the finding of new therapeutic approaches is imperative. In this review, we discuss the importance of the interaction between the endothelium and the tumor cells in brain and CNS malignancies. The different mechanisms of formation of new vessels that supply the tumor with nutrients are discussed. We also describe how the tumor cells (TC) alter the endothelial cell (EC) physiology in a way that favors tumorigenesis. In particular, mechanisms of EC-TC interaction are described such as (a) communication using secreted growth factors (i.e., VEGF, TGF-β), (b) intercellular communication through gap junctions (i.e., Cx43), and (c) indirect interaction via intermediate cell types (pericytes, astrocytes, neurons, and immune cells). At the signaling level, we outline the role of important mediators, like the gasotransmitter nitric oxide and different types of reactive oxygen species and the systems producing them. Finally, we briefly discuss the current antiangiogenic therapies used against brain and CNS tumors and the potential of new pharmacological interventions that target the EC-TC interaction.

Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. VEGF was reported to promote the occurrence of autophagy, which enhanced the radioresistance of tumors. The purpose of this study was to investigate the influence of VEGF silencing on the radiosensitivity of nasopharyngeal carcinoma (NPC) cells and the underlying mechanisms. The radiosensitivity of NPC cells after VEGF silencing was detected by cell counting kit 8 (CCK-8) and clonogenic assay, while cell cycle and apoptosis were detected by flow cytometry. The processes of DNA damage, repair and autophagy were examined by immunofluorescence and western blotting. The interaction between VEGF and mTOR was confirmed by western blotting and co-immunoprecipitation studies. The effect of VEGF on radiosensitivity of NPC cells was investigated in vivo using a xenograft model. Furthermore, immunohistochemistry and TUNEL assays were used to verify the relationship between autophagy and radiosensitivity in NPC after VEGF depletion. Downregulation of VEGF significantly inhibited cell proliferation and induced apoptosis of NPC cells after radiotherapy in vitro and in vivo. In addition, VEGF knockdown not only decreased autophagy level, but also delayed the DNA damage repair in NPC cells after irradiation. Mechanistically, silencing VEGF suppressed autophagy through activation of the mTOR pathway. VEGF depletion increased radiosensitivity of NPC cells by suppressing autophagy via activation of the mTOR pathway.

Pathological angiogenesis of the retina is a key component of irreversible causes of blindness, as observed in proliferative diabetic retinopathy (PDR). The pathogenesis of PDR is complex and involves vascular, inflammatory, and neuronal mechanisms. Several structural and molecular alterations associated to PDR are related to the presence of inflammation that appears to play a non-redundant role in the neovascular response that characterizes the retina of PDR patients. Vascular endothelial growth factor (VEGF) blockers have evolved over time for the treatment of retinal neovascularization. However, several limitations to anti-VEGF interventions exist. Indeed, the production of other angiogenic factors and pro-inflammatory mediators may nullify and/or cause resistance to anti-VEGF therapies. Thus, appropriate experimental models are crucial for dissecting the mechanisms leading to retinal neovascularization and for the discovery of more efficacious anti-angiogenic/anti-inflammatory therapies for PDR patients. This review focuses on the tight cross talk between angiogenesis and inflammation during PDR and describe how the chick embryo chorioallantoic membrane (CAM) assay may represent a cost-effective and rapid in vivo tool for the study of the relationship between neovascular and inflammatory responses elicited by the vitreous humor of PDR patients and for the screening of novel therapeutic agents., (Copyright © 2020 Rezzola, Loda, Corsini, Semeraro, Annese, Presta and Ribatti.)

The paracrine secretion of angiogenic cytokines from adipose-derived stem cells (ADSCs) might promote endothelial cell angiogenesis, therefore promoting wound healing in injured tissues. Hypoxia is one of the common occurrence in injured tissues, during which angiogenesis is enhanced to improve the oxygen supply. In the present study, miR-590-3p, an anti-angiogenic miRNA, was predicted to target VEGFA, a key factor that can be transcriptionally upregulated by HIF1A during ADSC proliferation and tubule formation in response to hypoxic stimulation. Herein, we found that in response to hypoxic stimuli, HIF1A and VEGFA protein expressions were remarkably induced. In addition, ADSC viability was promoted. Incubation with conditioned medium from ADSCs stimulated by hypoxia significantly enhanced the angiogenic ability of human dermal microvascular endothelial cells (HDMECs), while the conditioned medium from VEGFA-silenced ADSCs significantly reversed the angiogenic ability of HDMECs. Regarding the molecular mechanism, it was verified that miR-590-3p binds to VEGFA; miR-590-3p inhibited VEGFA to affect the paracrine regulation by ADSCs, subsequently hindering the HDMEC angiogenesis. More importantly, the consequences of miR-590-3p-overexpressing conditioned medium on HDMEC angiogenesis were partially reversed by VEGFA-overexpressing conditioned medium. In conclusion, miR-590-3-5p/VEGFA axis modulates the paracrine secretion of VEGFA by ADSCs to affect the angiogenesis of HDMECs.

The kidney contains a network of lymphatic vessels that clear fluid, small molecules, and cells from the renal interstitium. Through modulating immune responses and via crosstalk with surrounding renal cells, lymphatic vessels have been implicated in the progression and maintenance of kidney disease. In this Review, we provide an overview of the development, structure, and function of lymphatic vessels in the healthy adult kidney. We then highlight the contributions of lymphatic vessels to multiple forms of renal pathology, emphasizing CKD, transplant rejection, and polycystic kidney disease and discuss strategies to target renal lymphatics using genetic and pharmacologic approaches. Overall, we argue the case for lymphatics playing a fundamental role in renal physiology and pathology and treatments modulating these vessels having therapeutic potential across the spectrum of kidney disease., (Copyright © 2020 by the American Society of Nephrology.)